Figure 1: Hypothesis of SPION-sODN detection: All living cells takes up DNA-conjugated SPION (SPION-sODN), most likely by endocytosis (Figure 1B). The living brain keeps bound nucleic acid along with the contrast agent (Figure 1C), but neural cells excludes free, unbound single-stranded DNA and non-targeting SPION at physiological temperature (Figure 1D), whereby a window of detection is created for MRI based on preferential retention of SPION-sODN-mRNA, either by MRI in vivo (Figure 1C1) or by optical imaging and transmission electron microscopy in vitro (Figure 1C2). If the concentration of targeting sODN is high enough to overcome exclusion for a longer time, a gene transcript knockdown effect is created which can have therapeutic effect (Figure 1C3). Although the exclusion mechanism is not totally understood, we will show additional evidence to support that mRNA tagging in vivo is based on Watson-Crick hybridization between two complementary sequences in physiological condition, except conventional molecular assays in vitro are affected by changes between high and low temperatures during hybridization.